Brigida, I, Sauer, AV, Ferrua, F, Giannelli, S, Scaramuzza, S, Pistoia, V, Castiello, MC, Barendregt, BH, Cicalese, MP, Casiraghi, M, Brombin, C, Puck, J, Muller, K, Notarangelo, LD, Montin, D, Van Montfrans, JM, Roncarolo, MG, Traggiai, E, Van Dongen, JJM, Van Der Burg, M and Aiuti, A (2014) B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients. Journal of Allergy and Clinical Immunology. pp. 799-806.

Abstract

Background Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. Objective We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Methods Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Results Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. Conclusions ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT. 2013 American Academy of Allergy, Asthma and Immunology

Item Type:	Article
Additional Information:	NIBR author: Traggiai, E institute: NIBR contributor address: (Brigida, Sauer, Giannelli, Scaramuzza, Pistoia, Castiello, Roncarolo, Aiuti) San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy (Aiuti) Department of Systems Medicine, Tor Vergata University, Rome, Italy (Ferrua, Cicalese, Casiraghi) Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy (Castiello, Roncarolo) Vita-Salute San Raffaele University, Milan, Italy (Barendregt, Van Dongen, Van Der Burg) Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands (Brombin) CUSSB, Vita-Salute San Raffaele University, Milan, Italy (Puck) Division of Allergy, Immunology and Bone Marrow Transplantation, Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States (Muller) Pediatric Clinic, Juliane Marie Center, Copenhagen, Denmark (Notarangelo) Pediatric Onco-Hematology and BMT Unit, Children's Hospital, Spedali Civili, Brescia, Italy (Montin) Department of Pediatrics, University of Turin, Turin, Italy (Van Montfrans) Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands (Traggiai) Novartis Institute for Research in Biomedicine, Basel, Switzerland
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22605